Abstract: The functional cure of the ?Berlin Patient? through transplantation of allogeneic CCR5?32 stem cells advocates for using gene-altered stem cells to confer lifetime protection against HIV-1 re-infection. Large-scale adoption of allogeneic transplantation of CCR5?32 stem cells is not possible however. The barriers to stem cell transplantation as a therapeutic option for HIV will be significantly lowered if gene-editing platforms could be used to safely and efficiently generate patient-specific CCR5 null CD34+ HSCs for autologous transplantation. At the same time, it is also clear that eradication of HIV reserves will be an important part of an effective and durable HIV cure. In this multi- disciplinary proposal we will apply several cutting edge technologies including modified-mRNA and CRISPR/Cas9 gene-editing platforms to engineer CD34+ hematopoietic stem cells and CD8+ T-cells towards the goals generating HIV- resistant immune systems, and eradicating viral reserves.